title: A single replacement of histidine to arginine in EGFR-lytic hybrid peptide demonstrates the improved anticancer activity.
abstract: We previously reported that novel targeted "hybrid peptide" in which epidermal growth factor receptor (EGFR) binding peptide was conjugated with lytic-type peptide had selective cytotoxic activity to EGFR expressing cancer cell lines, and in vivo analysis revealed that this EGFR-lytic peptide displayed significant antitumor activity in a xenograft model of human breast cancer which was resistant to tyrosine kinase inhibitor drugs. As an attempt to improve the selective anticancer activity of EGFR-lytic peptide, we modified the EGFR-binding peptide through introducing the mutation of amino acid according to biophysical analysis by biomolecular interaction and circular dichroism (CD) spectra. When cytotoxic activity of EGFR-lytic or EGFR(2R)-lytic hybrid peptides was investigated in various human cancer and normal cell lines, it was demonstrated that EGFR(2R)-lytic, in which second histidine (H) of EGFR-binding peptide was replaced to arginine (R) had 1.2-1.9-fold higher cytotoxic activity than that of original EGFR-lytic peptide. In vivo analysis also revealed that this modified peptide displayed significant antitumor activity at as low as 1 mg/kg dosage. These results suggest that mutated arginine on EGFR-lytic peptide produces higher binding ability to EGFR on cancer cells, and thereby the improved anticancer activity.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tada
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Mari
authors.initials: M
authors.lastname: Haramoto
authors.forename: Koji
authors.initials: K
authors.lastname: Ohara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kohno
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D005260:Female; D006639:Histidine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011993:Recombinant Fusion Proteins; D006639:Histidine; D001120:Arginine; D066246:ErbB Receptors